Regorafenib and Nivolumab in Treating Regorafenib and Nivolumab in Mismatch Repair (MMR) Proficient Advanced Refractory Colorectal Cancer

Inclusion Criteria

• Histologically confirmed diagnosis of colorectal adenocarcinoma
• Proficient deoxyribonucleic acid (DNA) mismatch repair (MMR) or stable microsatellite disease confirmed by immunohistochemical staining or polymerase chain reaction (PCR)
• Patients with the presence of at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node by RECIST 1.1 for response assessment
• Patients must have received and progressed through or become intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab, and if K-ras wild type, cetuximab or panitumumab containing therapies. Prior TAS 102 is allowed
• Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
• Estimated life expectancy > 3 months
• Hemoglobin > 8.0 g/dl
• Absolute neutrophil count (ANC) > 1,000/mm3 independent of growth factor support
• Platelet count > 100,000/mm3
• Total bilirubin < 1.5 times upper limit of normal (ULN) unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 times the ULN (=< 5 x ULN for patients with liver involvement)
• Alkaline phosphatase =< 2.5 times the ULN (=< 5 x ULN for patients with liver involvement)
• Creatinine clearance, calculated according to the Cockroft-Gault formula, must be >= 30 ml/min
• Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy or experimental therapy within the 21 days prior to the start of regorafenib and nivolumab administration
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) performed within 24 hours prior to the start of study drug and then every 4 weeks. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 5 months for females and 7 months for males after the last dose of study drug
• Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other study requirements

Exclusion Criteria

• Subjects with active central nervous system (CNS) metastases. If CNS metastases are treated and subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be eligible but will need a brain magnetic resonance imaging (MRI) prior to enrollment
• Uncontrolled hypertension (systolic pressure > 140 mm Hg or diastolic pressure > 90 mm Hg [National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0] on repeated measurement) despite optimal medical management
• Active or clinically significant cardiac disease including: * Congestive heart failure – New York Heart Association (NYHA) > class II * Active coronary artery disease * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin * Unstable angina (angina symptoms at rest), new-onset angina within 3 months, or myocardial infarction within 6 months
• Women who are pregnant or breast-feeding
• Prior therapy with regorafenib, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways)
• Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
• Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks
• Patients with phaeochromocytoma
• Ongoing infection > grade 2 NCI-CTCAE v5.0
• Presence of a non-healing wound, or bone fracture
• Renal failure requiring hemo-or peritoneal dialysis
• Patients with seizure disorder requiring medication
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• Pleural effusion or ascites that causes respiratory compromise (>= NCI-CTCAE version 5.0 grade 2 dyspnea)
• Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation
• Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial
• Persistent proteinuria >= grade 3 NCI-CTCAE v5.0 (> 3.5 g/24 hours [hrs], measured by urine protein:creatinine ratio on a random urine sample)
• History of organ allograft
• Subjects requiring warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
• Subjects with a condition requiring a strong CYP3A4 inhibitors or strong CYP3A4 inducers
• Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or procedure, excluding alopecia
• Any hemorrhage or bleeding event >= NCI CTCAE grade 3 within 4 weeks prior to start of study medication
• Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
• Subjects with an arterial thrombotic or thromboembolic event within 6 months of informed consent
• Known history of human immunodeficiency virus (HIV) infection or current chronic or active hepatitis B or C infection
• Child-Pugh B cirrhosis (or worse) or a history of hepatic encephalopathy
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment
• Major surgery or a wound that has not fully healed within 4 weeks of enrollment
• Subjects requiring concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than study treatment
• Subjects requiring hormonal therapy during the study or within 2 weeks of first study enrollment